Am. J. Respir. Cell Mol. Biol.,
Volume 26, Number 6, June, 2002 731-738
Subinhibitory Bismuth-Thiols Reduce Virulence of
Pseudomonas aeruginosa
Chieh-Liang
Wu,
Philip
Domenico,
Daniel J.
Hassett,
Terry J.
Beveridge,
Alan R.
Hauser,
and
Jeffrey A.
Kazzaz
CardioPulmonary Research Institute, Divisions of Pulmonary and Critical Care Medicine and Infectious Disease, Winthrop-University
Hospital, SUNY School of Medicine at Stony Brook, Mineola, New York; Department of Molecular Genetics, Biochemistry, and
Microbiology, University of Cincinnati College of Medicine, Cincinnati, Ohio; Department of Microbiology and Canadian Bacterial
Disease Network - National Center of Excellence, University of Guelph, Ontario, Canada; and Departments of Microbiology/Immunology
and Medicine, Northwestern University School of Medicine, Chicago, Illinois
Pseudomonas aeruginosa is a common pathogen in mechanically ventilated patients and produces a wide array of virulence
factors. Bismuth-thiols (BTs) are active in vitro against all bacterial lung pathogens, including P. aeruginosa. The objective of
these studies was to examine the biochemical and morphologic
effects of sublethal BT concentrations on P. aeruginosa and to
evaluate virulence in cell culture. Bismuth-dimercaprol, at a
fraction of the minimal inhibitory concentration, reduced alginate expression by 67% in P. aeruginosa, whereas subinhibitory
bismuth-ethanedithiol (BisEDT) reduced alginate by 92% in P. syringae. BisEDT effects on lipopolysaccharide content and type
III secreted cytoxins were examined by sodium dodecyl sulfate
polyacrylamide gel electrophoresis. Subinhibitory BisEDT reduced cell-associated lipopolysaccharide, and inhibited processing of the secreted cytotoxic protein ExoU. BisEDT-induced
outer membrane blebbing and aggregation of cytoplasmic material was noted in electron microscopy. Virulence of P. aeruginosa was assessed by adherence to epithelial cells and sensitivity to serum killing. BisEDT inhibited adherence of P. aeruginosa to 16HBE14o
cells by 28% and to a collagen matrix by 53%.
BisEDT-treated bacteria were also 100-fold more sensitive to
serum bactericidal activity. In summary, low BT concentrations
affect P. aeruginosa in a variety of ways, the combination of
which may help prevent or resolve respiratory tract infection.
Abbreviations: bismuth dimercaprol, BisBAL; bismuth-ethanedithiol,
BisEDT; bismuth-thiols, BTs; cystic fibrosis, CF; exopolysaccharide, EPS;
fetal bovine serum, FBS; lipopolysaccharide, LPS; minimal bactericidal
concentration, MBC; minimal inhibitory concentration, MIC; trypticase
soy agar, TSA.
